Skp2 is over-expressed in breast cancer and promotes breast cancer cell proliferation

Zhang, Wenwen; Cao, Lulu; Sun, Zhixin; Xu, Jianping; Tang, Lin; Chen, Weiwei; Luo, Jiayan; Yang, Fang; Wang, Yucai; Guan, Xiaoxiang

doi:10.1080/15384101.2016.1160986

Cited by 41 publications

(34 citation statements)

References 40 publications

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“…Importantly, elevated levels of both p62 and Skp2 have been associated with therapeutic resistance 38 – 40 and as such. efforts are currently underway to identify small molecule inhibitors 37 , 39 , 41 – 43 to block their function and/or activity. While several reports indicate that autophagy plays a pro-survival role in a variety of cancers 44 , other studies indicate that autophagy induced by anti-neoplastic agents results in cell death 44 .…”

Section: Discussionmentioning

confidence: 99%

Quinacrine upregulates p21/p27 independent of p53 through autophagy-mediated downregulation of p62-Skp2 axis in ovarian cancer

Jung

Khurana

Roy

et al. 2018

Sci Rep

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We have previously shown that the anti-malarial compound Quinacrine (QC) inhibits ovarian cancer (OC) growth by modulating autophagy. In the present study we extended these studies to identify the molecular pathways regulated by QC to promote apoptosis independent of p53 status in OC. QC exhibited strong anti-cancer properties in OC cell lines in contrast to other anti-malarial autophagy inhibiting drugs. QC treatment selectively upregulated cell cycle inhibitor p21, and downregulated F box protein Skp2 and p62/SQSTM1 expression independent of p53 status. Genetic downregulation of key autophagy protein ATG5 abolished QC-mediated effects on both cell cycle protein p21/Skp2 as well as autophagic cargo protein p62. Furthermore, genetic silencing of p62/SQSTM1 resulted in increased sensitivity to QC-mediated apoptosis, downregulated Skp2 mRNA and increased accumulation of p21 expression. Likewise, genetic knockdown of Skp2 resulted in the upregulation of p21 and p27 and increased sensitivity of OC cells to QC treatment. In contrast, transient overexpression of exogenous p62-HA plasmid rescued the QC-mediated Skp2 downregulation indicating the positive regulation of Skp2 by p62. Collectively, these data indicate that QC-mediated effects on cell cycle proteins p21/Skp2is autophagy-dependent and p53-independent in high grade serious OC cells.

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Section: Discussionmentioning

confidence: 99%

Quinacrine upregulates p21/p27 independent of p53 through autophagy-mediated downregulation of p62-Skp2 axis in ovarian cancer

Jung

Khurana

Roy

et al. 2018

Sci Rep

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“…Since the original identification of PHB1 as a proliferation suppressor in rat liver cells 1 , the effect of PHB1 on cancer proliferation has been studied. Some studies found that PHB1 inhibits breast cancer cell proliferation by up-regulating androgen receptor (AR) expression in estrogen receptor (ER)-positive breast cancer cells 15 , 63 . PHB1 also inhibits proliferation of human osteosarcoma MG-63 cells by interacting with tumor suppressors such as p53 64 .…”

Section: Role Of Phb1 and Phb2 In Tumorigenesismentioning

confidence: 99%

Significance of prohibitin domain family in tumorigenesis and its implication in cancer diagnosis and treatment

Yang

2018

Cell Death Dis

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Prohibitin (PHB) was originally isolated and characterized as an anti-proliferative gene in rat liver. The evolutionarily conserved PHB gene encodes two human protein isoforms with molecular weights of ~33 kDa, PHB1 and PHB2. PHB1 and PHB2 belong to the prohibitin domain family, and both are widely distributed in different cellular compartments such as the mitochondria, nucleus, and cell membrane. Most studies have confirmed differential expression of PHB1 and PHB2 in cancers compared to corresponding normal tissues. Furthermore, studies verified that PHB1 and PHB2 are involved in the biological processes of tumorigenesis, including cancer cell proliferation, apoptosis, and metastasis. Two small molecule inhibitors, Rocaglamide (RocA) and fluorizoline, derived from medicinal plants, were demonstrated to interact directly with PHB1 and thus inhibit the interaction of PHB with Raf-1, impeding Raf-1/ERK signaling cascades and significantly suppressing cancer cell metastasis. In addition, a short peptide ERAP and a natural product xanthohumol were shown to target PHB2 directly and prohibit cancer progression in estrogen-dependent cancers. As more efficient biomarkers and targets are urgently needed for cancer diagnosis and treatment, here we summarize the functional role of prohibitin domain family proteins, focusing on PHB1 and PHB2 in tumorigenesis and cancer development, with the expectation that targeting the prohibitin domain family will offer more clues for cancer therapy.

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“…Analysis of the cell cycle and apoptosis was performed as described previously. [26][27][28][29] Each sample was tested in triplicate and untreated cells were used as controls.…”

Section: Cell Cycle and Apoptosis Analysismentioning

confidence: 99%

Prohibitin promotes androgen receptor activation in ER-positive breast cancer

Liu

Zhang

et al. 2017

Cell Cycle

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Prohibitin (PHB) is an evolutionarily conserved protein with multiple functions in both normal and cancer cells. Androgen receptor (AR) was reported to act as a different role in the ER-positive and ER-negative breast cancer. However, little is known about the role of PHB and whether PHB could regulate AR expression in the ER-positive breast cancer. Here, we determined the expression and clinical outcomes of PHB in breast cancer samples using 121 breast cancer tissues and published databases, and investigated the role of PHB in breast cancer cell growth, apoptosis and cell cycle arrest in the ER-positive breast cancer cells. We obtained the expression of PHB is significantly low in breast cancer samples, and low PHB expression positively correlated with poor prognosis of breast cancer. We detected that PHB could inhibit breast cancer cell proliferation, change cell cycle distribution and promote cell apoptosis in the ER-positive breast cancer cells. Moreover, we found PHB could significantly increase AR expression in both mRNA and protein levels in the ER-positive breast cancer cells. Additionally, a significant positive correlation between PHB and AR expression was identified in the 121 breast cancer tissues. PHB and AR expression are associated with prognosis in the ER-positive breast cancer patients. Our results indicate that PHB promotes AR activation in ER-positive breast cancer, making PHB and AR potential molecular targets for ER-positive breast cancer therapy.

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Skp2 is over-expressed in breast cancer and promotes breast cancer cell proliferation

Cited by 41 publications

References 40 publications

Quinacrine upregulates p21/p27 independent of p53 through autophagy-mediated downregulation of p62-Skp2 axis in ovarian cancer

Quinacrine upregulates p21/p27 independent of p53 through autophagy-mediated downregulation of p62-Skp2 axis in ovarian cancer

Significance of prohibitin domain family in tumorigenesis and its implication in cancer diagnosis and treatment

Prohibitin promotes androgen receptor activation in ER-positive breast cancer

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